This is a resubmission of a competitive renewal application of the Collaborative Study of Ovarian Cancer (R01- CA58598), a population-based case-control study in its second funding cycle. In this application, we follow-up on several leads from our data to examine a novel role for the vitamin D endocrine / signaling pathway in the etiology of ovarian cancer associated with proteolytic degradation of the ovulatory follicle, as well as post- ovulatory tissue remodeling that accompany healing and repair of the traumatized ovarian tissue. In addition to the genes involved with vitamin D metabolism, we have included key signaling pathways targeted by vitamin D and its receptor complex that influence the dynamic equilibrium between the extracellular matrix and ovarian epithelial cells during the wounding and repair associated with ovulation. The ovarian surface epithelium is subject to repeated wounding and healing during ovulation. It is thought that this repeated proliferative stimulation may be a key pathway to the malignant transformation of ovarian epithelial cells. The study methodology is based on a three-stage design within the Ovarian Cancer Association Consortium in which we will examine genetic variation in the vitamin D endocrine / signaling pathway that might influence the risk of ovarian cancer. Aim 1 will include a two-stage analysis of 2,930 cases and frequency-matched controls, identified in Hawaii and six other geographic areas, to identify common variants among ~3000 tagSNPs in genes that may be related to the malignant transformation of the ovary. In Aim 2 (Stage 3), we will conduct a validation study of a reduced set of ~62 (~2%) of the most promising SNPs from Aim 1 among 5,236 OvCa cases and frequency-matched controls in an independent set of six case-control studies. As part of our analysis, we will examine gene-environment and gene-gene interactions. This study fulfills key missions of the NCI's Epidemiology and Genetics Research Program by potentially providing new insights into the biology of ovarian malignancy and into the complex interactions of host genetics with environment and lifestyle in the carcinogenic process. The identification of ovarian cancer susceptibility genes that are related to ovarian surface epithelium tissue remodeling might shed light on novel vitamin D-associated enzymatic pathways in this malignancy. PUBLIC HEALTH RELEVANCE: Although ovarian cancer only accounts for 3% of new malignancies among women in the U.S., it is the fifth most common cause of cancer mortality and is the cause of 6% of all cancer deaths. There is an urgent need to establish a panel of genetic variants associated with ovarian cancer susceptibility that can be used in combination with known epidemiological risk factors to identify higher-risk women. The identification of ovarian cancer susceptibility genes that are related to OSE wounding and post-ovulatory tissue remodeling might shed light on important vitamin D-associated pathways in the carcinogenic process.